Hep B and C: Updates and Resources John Scott, MD, MSc Asilomar AETC Conference October 6, 2006.

Slides:



Advertisements
Similar presentations
Hepatitis B & Hepatitis C in HIV
Advertisements

Egyptian Guidelines For Management of Chronic Hepatitis B
HBV and HIV HIV and HBV VG Naidoo Gastroenterology.
Hcv infection and management in advanced liver disease
Alfredo ALBERTI. How to predict outcome in hepatitis C patients Alfredo Alberti Department of Clinical and Experimental Medicine Venetian Institute of.
The Hepatitis B&C Past and Present Martin J Spitz MD FACP AGAF Clinical Professor of Medicine UCSF.
Optimal therapy in genotype 2 and 3 patients Antonio Craxì Liver & GI Unit, Di.Bi.M.I.S., University of Palermo, Italy
Treatment appropriate Normal or minimal hepatitis Chronic hepatitis Normal or inactive hepatitis Progressive fibrosis Cirrhosis HCC HBeAg Anti-HBe HBV.
Professor George KK Lau The University of Hong Kong Hong Kong SAR, China HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated.
BORDERNETwork Training on HIV and HBV Co-Infections Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A.
Case study: Chronic HBV infection Marion Peters University of California San Francisco 2009.
Hepatitis web study H EPATITIS W EB S TUDY Therapeutic Agents Used to Treat Hepatitis B Presentation Prepared by: Nina Kim, MD and David Spach, MD Last.
1 3 rd Paris Hepatitis Congress, 20/1/09 HBeAg-positive patient: Why do I treat with nucleos/tide analogs? Samuel S. Lee University of Calgary Calgary,
HIV/HBV coinfection in HIV-infected children Pope Kosalaraksa, M.D. Department of Pediatrics Faculty of Medicine Khon Kaen University.
Management of HIV infection in HIV/HCV co-infected patients Mark Hull, MD, MHSc, FRCPC Division of AIDS University of British Columbia.
Natural History of Hepatitis B and Liver Cancer Screening Herbert H Lee, M.D., M.P.H., M.S.Ed.
Long-Term Anti-HBV Therapy Considerations Adrian M. Di Bisceglie, MD, FACP Badeeh A. & Catherine V. Bander Chair in Internal Medicine Chairman and Professor.
Hepatitis web study Hepatitis web study PEG alfa-2a + RBV versus PEG alfa-2a versus INF + RBV APRICOT STUDY Phase 3 Treatment Naïve, Chronic HCV and HIV.
Hepatitis web study Hepatitis web study Peginterferon alfa-2a + RBV versus Interferon alfa-2a + RBV ACTG 5071 Phase 2 Treatment Naïve, Chronic HCV and.
Hepatitis B, C, and Beyond John Scott, MD, MSc Feb 20, 2007 Harborview Medical Center.
Slide #1 CL Thio, MD. Presented at RWCA Clinical Update, August Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals Chloe L. Thio,
Coinfection with Hepatitis B and HIV Chia C. Wang Assistant Professor of Medicine AIDS Clinical Conference February 20, 2007.
3 rd Paris Hepatitis Conference January, 20th 2009 How to optimize the management of my HBeAg negative patients? Pietro Lampertico 1st Gastroenterology.
Module 6: Treatment options. Module goal To enable participants understand the best current treatment options, factors that influence outcomes and potential.
Stefan ZEUZEM.
1 Hepatitis B Treatment Dr R.V.S.N.Sarma., M.D., Consultant Physician & Chest Specialist.
HIV and Hepatitis C Co-infection Amy Kindrick, M.D., M.P.H. San Francisco AIDS ETC National HIV/AIDS Clinical Consultation Center February 12, 2002.
Welcome to I-TECH HIV/AIDS Clinical Seminar Series HIV and Viral Hepatitis (B & C) H. Nina Kim, MD MSc University of Washington July 9, 2009.
Norah Terrault, MD, MPH Adjunct Assistant Professor,
Hepatitis C Virus Infection Hepatitis C Virus Infection Burden of Disease in United States New infections (cases)/year , ,000 Persons.
Hepatitis B: Chronic Hepatitis and Inactive Carriers - Management
Viral Hepatitis ( Useful Points for GPs in W Herts) Dr Alistair King Consultant Gastroenterologist Hemel Hempstead General Hospital.
John Scott, MD, MSc Infectious Diseases Fellows Course July 7, 2011.
Renal Transplantation for HIV/HCV Co-infected Patients Solid Organ Transplantation and People With HIV: Ethics and Policy Conference David Oldach & Robert.
Abstract Results Objectives Results Conclusions Background Methods V-1637 Background-At the CORE center in Chicago, despite an on-site hepatitis clinic.
This is the most comprehensive compilation of epidemiological information on Hepatitis C Graciously provided by the University Hepatitis Center (last updated.
Hepatitis C: The Next Tsunami Danny Jenkins Cri-Help Common Ground – The Westside HIV Community Center We Write the Grants
HBV genotyping 12/21/07 Carrie Marshall. Received a send-out request for HBV genotyping on a 52y man.
Hepatitis B Patricia D. Jones, M.D. November 13, 2009.
Update on the HCV Antiviral Pipeline Todd S. Wills, MD SPNS HCV Treatment Expansion Initiative Evaluation and Technical Assistance Center Infectious Disease.
1. Sustained suppression of HBV replication Decrease in serum HBV DNA to
Current treatment of hepatitis C in HIV co-infected patients Dominique SALMON Internal Medicine Department, COCHIN Hospital Paris, FRANCE 12th ISVHLD -
Yves BENHAMOU. Management of Patients with HIV/HBV Co-infection Yves Benhamou Hepatology Department Groupe Hospitalier Pitié Salpétrière Paris, France.
Twice Weekly Peg-IFN-alpha-2a with Ribavirin Improves Early Viral Kinetics over Standard Therapy Among HIV/HCV Co-Infected African American Patients Alison.
How to manage G1 relapsers and non-responders George V. Papatheodoridis, MD Associate Professor in Medicine & Gastroenterology 2nd Department of Internal.
Treating HBV Infection: Sustained Remission with Immune control Joseph Sung MD, PhD Department of Medicine and Therapeutics Institute of Digestive Diseases.
Hepatitis web study H EPATITIS W EB S TUDY H EPATITIS C O NLINE Ribavirin (Copegus, Rebetol, Ribasphere) Prepared by: David Spach, MD and H. Nina Kim,
Sources of Hepatitis C Infection (U.S.) Previously Acquired (
Hepatitis B The Basics David Wong University of Toronto March 2005.
Isolated Hepatitis B Core Antibody
On-treatment management for chronic hepatitis B (CHB) in patients receiving oral antiviral therapy Byung-Ho Kim Kyung Hee University School of Medicine.
내과스텝강의 국내 만성B형간염의 현황과 치료 전략.
Liver transplantation for HCV infection R3 양 인 호 /Prof 김 병 호.
Maria Buti, MD Professor of Medicine Hospital Universitario Vall d'Hebron Barcelona, Spain Clinical Focus: Impact of HBV Therapy on Liver Fibrosis and.
Viral hepatitis overview Itodo Ewaoche 27/02/2015.
Choosing First-Line Therapy in Chronic Hepatitis B This program is supported by an unrestricted educational grant from.
Clinicaloptions.com/hepatitis Using Virologic and Serologic Tests in the Management of Hepatitis B Diagnose chronic HBV infection When in slideshow mode,
Entecavir Superior to Lamivudine for Treatment of Nucleoside-Naive, HBeAg- Negative Patients Slideset on: Lai CL, Shouval D, Lok AS, et al. Entecavir versus.
HBV. Overview of the Epidemiology of Hepatotropic Viruses.
بنام خداوند مهربان. دکتر نرگس نجفی دانشیار دانشگاه.
Hepatitis B virus infection in renal transplant recipients
Telbivudine Versus Lamivudine in Chinese Patients with Chronic Hepatitis B: Results at 1 Year of a Randomized, Double-Blind Trial HEPATOLOGY 2008;47:
Viral Hepatitis.
A. Stepanov, A. Kruk, N. Polovinkina, A. Vinogradova
How to optimize the management of my HBeAg negative patients?
Simeprevir in HIV Coinfection, GT-1 C212 Trial
Clinicaloptions.com/hepatitis Using Virologic and Serologic Tests in the Management of Hepatitis B Diagnose chronic HBV infection When in slideshow mode,
Progression of chronic Hepatitis B From beginning to end
HEPATITIS B VIRUS ; WHAT`S NEW
Presentation transcript:

Hep B and C: Updates and Resources John Scott, MD, MSc Asilomar AETC Conference October 6, 2006

Outline Hepatitis C –Background & natural history –Treatment of Hep C/HIV coinfection New drugs Guidelines and Internet resources Hepatitis B –Natural history w/ and w/o HIV –Treatment of Hep B monoinfection –Treatment of Hep B/HIV coinfection New drugs Guidelines and Internet resources

Biology ss RNA virus RNA-dependent RNA polymerase, lacks proofreading function Flaviviridae 6 genotypes, type 1 accounts for 70% of infections in US, types 2,3 account for rest No easy culture system!

Liver Disease has Emerged as a Major Cause of Death in the HAART Era Bica Clin Infect Dis 2001; Puoti JAIDS 2000; Soriano Eur J Epidemiol 1999; Soriano PRN Notebook 2002; Martin-Carbonero AIDS Res Human Retrovirus Mortality (%) Death from end-stage liver disease (ESLD) as a % of all deaths among HIV patients Italy (Brescia)Spain (Madrid)USA (Boston) 13% 35% 5% 12% 45% 50% Pre-HAART era HAART era

Impact of HIV on HCV Cirrhosis Decompensation Makris Soto Pol Benhamou Combined Eyster Telfer Makris Lesens Combined Graham CID 2001 Relative Risk (95% CI) AB

AASLD Guidelines Anti-HCV testing on all HIV+ pts HCV RNA to confirm Ab+ and all Ab- w/ unexplained liver disease Treat HIV/HCV patients in whom likelihood of serious liver dz and tx response outweigh the side effects of tx PegIFN-alfa + ribavirin x 48 wks Closely monitor pts on therapy Use RVN carefully in pts on AZT or d4T. Avoid RVN and ddI Decompensated liver dz -> liver transplant eval Strader D. Hepatology 2004.

Workup H&P: date HCV diagnosed, risk factors, earliest exposure, signs and symptoms of hepatitis and cirrhosis, alcohol hx, prior treatment and response Candidate for tx: depression, poorly controlled DM, CAD, cytopenias, autoimmune dz, pregnant EIA (TPR>99%, TNR=99%) If EIA+, sensitive PCR assay LFTs, CBC, chem 7, TSH, hepatitis serologies, CD4 and HIV RNA, pregnancy test, eye exam, utox? If treatment contemplated, then HCV genotype and viral load, +/- liver biopsy

Liver Biopsy Currently the best way to determine how much scarring is present, but imperfect Needle, local anesthetic Risks: bleeding Scar Stages: (Batts-Ludwig) VA guidelines recommend bx for all patients

Progression of Fibrosis on Biopsy No Fibrosis Stage 1: Fibrous expansion of some portal areas Stage 3: Fibrous expansion of most portal areas with occasional portal to portal bridging Stage 4: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) Stage 4: Cirrhosis Cirrhotic liver: Gross anatomy of cadaver Courtesy of Gregory Everson, MD.

ACTG 5071 (Chung RT, NEJM 2004; 351:451-9) RIBAVIC (Carrat F, JAMA 2004; 292: ) APRICOT (Torriani F, NEJM 2004: 351:438-50) –All compared standard with pegylated IFN –All treated for 48 weeks, regardless of genotype –All used low-dose RBV (avg dose 800 mg/d) Laguno et al (AIDS 2004: 18:27-36). –Higher dose RBV, 24 weeks for GT2 or 3 Prospective, Randomized Multicenter Trials of Pegylated Interferons in HIV/HCV

HIV/HCV Coinfection Trials ACTGRIBAVICAPRICOTLaguno # pts % genotype 178%66%61%49% fibrosis score % cirrhotic30% st 3 or 4 Mean CD Overall SVR27%26%40%44% SVR GT 15%15%29%38% SVR non-130%43%62%53% d/c rate (ea arm)12%42%30-40%17%

Side Effects of PegIFN/Ribavirin Depression ranging from mild to suicidality Irritability, aggressive behavior Worsening of mania Fatigue Insomnia Myalgias, fever, flu- like symptoms Hair loss Cytopenias “Interferon Man”

High relapse rate (33-44%) in HIV/HCV Torriani, F NEJM 351: Soriano, V AIDS Research Human Retrovirus 20:351-3.

Extended treatment for HCV Mathematical models show that viral suppression necessary for at least 36 weeks HCV monoinfected trial showed that if HCV RNA + at wk 12 but – at wk 24, SVR increased from 17% to 29% with add’l 24 weeks of therapy Goal: reduce relapse rate Drusano GL J Infect Dis 189: Berg T Gastro 130:

Duration of Detectability (DUD) Time (weeks) RVR EVR Slow VR Detectable Undetectable 44 wks 36 wks 24 wks Ferenci 2005, Fried 2006

PRESCO Ongoing Spanish study of 398 stable coinfected pts (mean CD4 562 cells/mm 3 ) All are receiving 180 mcg PegIFNα2a (Pegasys) and wt-based RBV (1000 or 1200 mg/d) Comparing extended tx w/ std tx: –48 weeks for GT non-1 –72 weeks for GT 1 Soriano, et. al., 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) October 30 - November 2, 2004, Washington, DC (abstract)

% HCV Responders at Week 4 GenotypeStudy# patientsHCV-RNA reduction > 1 log 10 HCV-RNA reduction > 2 log 10 Serum HCV-RNA- negative Genotype 1 PRESCO Fried APRICOT Genotype 3 PRESCO Fried APRICOT Soriano V. 2 nd Intl Workshop on HIV and HCV 2006

PRESCO: Interim Analysis End-of-treatment results for 181 pts: –Overall, 63% response rate –50% for GT 1 –85% for GT 2/3 Highest response rates reported so far for coinfected pts.

HRN-004SLAM-CENDURE Patient populationNonresponse F > 0/CPT < 6 Any F > 0/CPT < 6 Any CPT ≤ 8 Number of patients EndpointHistology/clinic al Clinical Arm 1PEG-IFN alfa 2a 90 mcg PEG-IFN alfa- 2a 180 mcg PEG-IFN alfa 2b 0.5 mcg/kg Arm 2Observation Treatment duration (years) 1.5 Recruitment statusCompleteEnrollingLaunch nd Intl Workshop on HIV and HCV 2006 Maintenance Therapy Trials for Prior Non-responders

Drugs in development Serine protease inhibitors Polymerase inhibitors Helicase inhibitors Antisense therapy siRNA Toll-like receptor agonists Therapeutic vaccination Cyclosporine analog Improved Ribavirin and Interferon Review: McHutchison JG J Hepatol 44: Source:

Hepatitis B: Epidemiology HBV very common worldwide, ~350 million infected 1.25 million Americans chronically infected 70,000 new cases annually in US HBV is 10x more common in HIV+ than in general population Highest rates among HIV+ seen in MSM (6-10%) Keeffe EB, et al. Clin Gastroenterol Hepatol Nunez M, et al. Lancet Infect Dis 2005.

Clinical-Epidemiologic Correlations HBV Endemicity Location Age of Infection Mode of Transmission Chronicity HCC Risk High 10-15% Asia Sub-Sahara Africa Birth Toddler Perinatal Horizontal LikelyHigh Low < 2% N. America W. Europe Scandinavia Early Adulthood Percutaneous Sexual RareLow Available at: Accessed February 6, Designed by Jules Dienstag, MD clinicaloptions.com/hep

Prevalence of Chronic Hepatitis B HBsAg Prevalence > 8% - High 2-8% - Intermediate < 2% - Low Immigration numbers summed by continent from ~ 2 million Asians ~ 400,000 South Americans ~ 350,000 Africans ~ 930, 000 Europeans Centers for Disease Control. Hepatitis B fact sheet. Available at: Accessed January 31, Mahoney FJ. Clin Microbiol Rev. 1999;12: Hepatitis B Foundation. Hepatitis B statistics. Available at: Accessed January 31, clinicaloptions.com/hep

Natural History of Chronic HBV Infection Years Serology HBeAgAnti-HBe ALT level HBV DNA level (viremia) Disease Chronic active hepatitis Cirrhosis/HCC Immune tolerant (phase I) Immune Active (phase II) Non-Replicative (phase III) Chronicity Stage Minimal inflammation Resolved Normal to cirrhosis/HCC HBsAgAnti-HBs clinicaloptions.com/hep

Outcomes of Acute HBV Infection Recover Subclinical Hepatitis Fulminant Hepatitis Acute Hepatitis ACUTE INFECTION Chronic Infection DEATH < 1% % 5-20% Risk is Related to Age at Infection OutcomeNeonates, %Children, %Adults, % Chronic carrier9020< 5 Recover1080> 95 Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25. clinicaloptions.com/hep

Possible Outcomes of HBeAg+ Chronic HBV Infection Patient Populations in Chronic Hepatitis B Marker Immune Tolerant HBeAg+ CHB Inactive HBsAg Carrier HBeAg– CHB (Precore Mutant) HBsAg++++ HBeAg++–– Anti-HBe––++ ALTNormal   HBV DNA (copies/mL) > 10 5 < 10 3 > 10 4 HistologyNormal/MildActiveNormalActive Lai CL, et al. Lancet. 2003:362: Lok AS, et al. Gastroenterology. 2001;120: clinicaloptions.com/hep

Annual Risk of HBV Progression HBeAg+ chronic hepatitis B HBeAg-Neg chronic hepatitis B Cirrhosis Decompensation HCC 5.0% 1.0%-2.0% 3.0%2.0% All HBsAg + individuals 0.4%  Factors linked with progression – Duration of “active”disease – Heavy alcohol use – Immune suppression (HIV) Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25. clinicaloptions.com/hep

HBV DNA Level and Risk of HCC HBV DNA (copies/ml) Cumulative incidence of HCC < ,000-99, , , >1 million14.89 Chen C-J. JAMA 2006; 295:67-73.

HBV Treatment Guidelines HBeAg HBV DNA (IU/ml)* ALTManagement + < 20,000Normal # Follow, no treatment + ≥ 20,000Normal Consider biopsy; treat if diseased + ≥ 20,000ElevatedTreat – < 2,000Normal Follow, no treatment – ≥ 2,000Normal Consider biopsy; treat if diseased – ≥ 2,000ElevatedTreat *1 IU = 5.6 copies; # Normal ALT for men = 30 U/ml and for women = 19 U/ml Keeffe EB, et al. Clin Gastroenterol Hepatol.2006.

HBV/HIV Patient 41 yo gay white man with C3 HIV, hep B, cirrhosis eAg+, baseline HBV DNA 10 million copies/ml, ALTs in 40-50’s HIV well-controlled, CD4 787, HIV <30, on NVP, ddI, Kaletra (highly ARV experienced) Started on LAM 100 mg/d 9/05 Seen by me 6/06: VL 5.5 million, ALT 49 Any mistakes in treatment? What medication should we use next?

Goals of Therapy in Patients With Chronic HBV Infection Eradication of infection –HBsAg seroconversion –Undetectable HBV DNA Prevent complications of liver disease –Histologic progression to cirrhosis –Decompensated liver disease –Liver cancer clinicaloptions.com/hep

Therapeutic Endpoints HBeAg-positive patients (wild type) –HBeAg seroconversion is KEY –Sustained suppression of HBV DNA to low or undetectable levels –ALT normalization –Reduced necroinflammation on biopsy HBeAg-negative patients (precore and core promoter mutants) –HBeAg seroconversion not an endpoint –Sustained suppression of HBV DNA to low or undetectable levels –ALT normalization –Reduced necroinflammation on biopsy clinicaloptions.com/hep

Approved anti-HBV drugs and those in development DrugClassPhaseAnti-HIVActive against YMDD Interferon-  Immune modulator ApprovedYes Peg-IFN-  ImmuneApprovedYes LamivudineNucleosideApprovedYesNo AdefovirNucleotideApprovedWeakNo EntecavirNucleosideApprovedYes TenofovirNucleotideIYes FTCNucleosideIYesNo TelbivudineNucleosideIIINo ClevudineNucleosideIIINoYes DAPDNucleosideIIYes Nunez M, et al. Lancet Infect Dis 2005.

Responses to anti-HBV agents in HIV/HBV coinfected patients IFNLAMADVETVFTCTDF # pts HBV DNA ↓ 26%2.7 log4.7-6 log3.6 log-4.4 log E sero- Convert 9%11%7%--4% ALT normalize 12-20%30-50%35-66%49%-- Histology improve %--- Benhamou Y. J Hepatol 2006.

HBV Treatment Algorithm in HIV/HBV Coinfected Patients HBVsAg-positive ALT HBVeAg HBV DNA >10 4 Biopsy Normal Elevated Negative Positive No Yes Normal Hepatitis Rx Nunez M. Lancet Infect Dis 2005

Lamivudine (3TC, Epivir) Nucleoside analog Different dose for HBV (100 mg) monotherapy, use 300 mg for HIV+ and never alone Well-tolerated and cheap eAg conversion rate b/t 21-28% High rates of resistance! –47% develop YMDD mutation at 2 yrs, 90% at 4 yrs

Adefovir (Hepsera) Nucleotide analog At 10 mg/d dose, no HIV activity Effective for LAM resistant HBV, no cross- resistance Side effects: renal toxicity, Fanconi’s Syndrome

Tenofovir (Viread) Nucleotide analog not approved for HBV Perhaps more potent than Adefovir –48 wk mean decline in HBV DNA (log10) 4.4 vs % had HBV suppression by wk 48, 15% had anti-HBe seroconversion Rare cases of ADV resistance but TDF sensitivity Schildgen O N Engl J Med 354: Peters M. CROI 2005; Abstract 124.

Entecavir (Baraclude) Nucleoside analog No HIV activity Good for LAM failures –84% of patients had 2 log decline or <400 copies/ml after 24 wks Cross-resistance can occur w/ LAM Start w/ higher dose (1.0 mg/d) Entecavir in HIV/HBV patients

Peg-interferon (Pegasys) Long acting form of IFN, once weekly Pros: defined duration (48 wks), low resistance Cons: Many side effects, expensive, not for decompensated cirrhosis No data in HIV+, probably lower response than in HIV- In HIV-, PEG better than LAM –27% seroconversion, 4.5 log HBV DNA reduction, 3% sAg loss

Treatment Options for HIV/HBV Coinfected Patients Only HBV therapy indicated HBeAg-positivePegylated IFN Entecavir Adefovir HBeAg-negativeEntecavir Adefovir HIV and HBV therapy indicated HAART including TDF +/- LAM or FTC HAART + (ADV or ETV) Only HIV therapyAt least one HBV active drug to avoid flares Nunez. Lancet Infect Dis 2005.

Back to the patient 41 yo gay white man with C3 HIV, hep B, cirrhosis eAg+, baseline HBV DNA 10 million copies/ml, ALTs in 40-50’s HIV well-controlled, CD4 787, HIV <30, on NVP, ddI, Kaletra (highly ARV experienced) Started on LAM 100 mg/d 9/05 Seen by me 6/06: VL 5.5 million, ALT 49 Any mistakes in treatment? What medication should we use next?

Web Resources ses/hepatitis/c/index.

Good Reviews Sulkowski MS. Treatment algorithm for the management of hepatitis C in HIV-coinfected person J Hepatol 44:S49-55 Nunez M, Soriano V. Management of patients coinfected with hepatitis B virus and HIV Lancet Infect Dis 5: Tien P, Wright T. Management and treatment of hepatitis C virus infection in HIV-infected Adults: Recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office Am J Gastro 100: Benhamou Y. Treatment algorithm for chronic hepatitis B in HIV-infected patients J Hepatol 44:S90-94.

Thanks!